There is substantial evidence that stress, emotional status and neural activity modulate immunological responsiveness. However, except for endocrine effects, the mechanism(s) of this regulation remain obscure at the cellular and molecular levels. One system that is amenable to establishing mechanistic links is the cutaneous immune system. In the skin, Langerhans cells (LCs), antigen presenting cells in the epidermis, are innervated. Furthermore, our laboratory has previously established that norepinephrine (NE), epinephrine (EPI) and three neuropeptides [calcitonin gene-related peptide (CGRP), pituitary adenylate activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP)] are all able to modulate cutaneous immune responses in vivo and in vitro. This neuro-immunological interaction is probably important in (a) some pathological conditions (atopic dermatitis, psoriasis, autoimmune disorders), (b) the normal responses to invading pathogens and (c) the response to antigens during vaccination. Nevertheless, there are substantial gaps in understanding these pathways. It is not known which intracellular signaling pathway(s) are responsible for mediating the effects of neurotransmitters or if different neurotransmitters influence different pathways. Although nerves influence Th1 responses, it is not clear if they influence Th2 responses or the balance of Th1 to Th2 responses. We propose herein to test the hypothesis that neurotransmitters modulate both Th1- and Th2-dependent immune responses by modulating intracellular signaling pathways, especially the cAMP-dependent inhibition of NFkappaB activation. A correlate of this hypothesis is that the nervous system may have a role in selecting the type of immune response that occurs. This will be done in 3 specific aims: Aim 1 - To identify and study the intracellular signaling events that mediate the effects of NE/EPI, PACAP, VIP, and CGRP on the maturation of LCs. Aim 2 - To determine if neuro-peptides or neurotransmitters modulate the Th2 response, the Th1/Th2 cytokine balance and/or antibody production. Aim 3 - To determine if denervation influences the number of LCs, their maturation state or their capacity to induce contact hypersen-sitivity. By further exploring the types of cutaneous immune responses that are regulated by the nervous system and by determining the molecular mechanisms of this regulation, we will create the knowledge needed for rational design of drugs to modify cutaneous immune responses in pathological and normal. Immune responses in the skin.